The serum complement cascade, the major humoral defense system, is activated by immune complexes through the classical pathway and by (lipo) polysaccharides through the alternative pathway. Serious pathologic effects of the autoimmune diseases could be ameliorated by pharmacologic modulation of the classical pathway. This project will explore the possibility of inhibiting the classical pathway while leaving the alternative and terminal lytic pathways functional. We have prepared synthetic peptide monomers and dimers from the 275-292 region of the gamma chain of the human immunoglobulin G1 protein Fu and found that a 24-residue dimer of the 281-292 region inhibits C1-mediated immune hemolysis as efficiently as the entire 1300-residue 7S form of human IgG1. Results with other peptides suggest that the C1-binding site of IgG contains the cationic 285-292 region (His-Asn-Ala-Lys-Thr-Lys-Pro-Arg). We shall synthesize related peptides and complexes that may bind tightly to C1q either with or without activation of the classical pathway. We have also synthesized several peptide inhibitors of C1s, the first physiologically accessible enzyme in the classical pathway. We shall synthesize additional peptide inhibitors and fluorescent peptide substrates of C1s. Finally, we have devised a hexapeptide thioester as a model of the labile reactive site of activated C4b. We shall synthesize this peptide and fluorescent analogues to explore its reaction kinetics with biological nucleophiles and receptive surfaces and the stability of the covalent bonds so formed. These studies will explore basic mechanisms of the classical complement pathway and may lead to useful peptide inhibitors of C1q, C1s, or C4b.